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J Natl Cancer Inst. 2019 Feb 1;111(2):146-157. doi: 10.1093/jnci/djy099.

Novel Common Genetic Susceptibility Loci for Colorectal Cancer.

Schmit SL1,2, Edlund CK2, Schumacher FR3, Gong J4, Harrison TA4, Huyghe JR4, Qu C2,4, Melas M2, Van Den Berg DJ2, Wang H5, Tring S2,6,7, Plummer SJ8, Albanes D9, Alonso MH10,11,12, Amos CI13, Anton K13, Aragaki AK4, Arndt V14, Barry EL15, Berndt SI9, Bezieau S4, Bien S16, Bloomer A1, Boehm J17, Boutron-Ruault MC18,19, Brenner H14,20,21, Brezina S22, Buchanan DD23,24,25, Butterbach K14, Caan BJ26, Campbell PT27, Carlson CS4, Castelao JE28, Chan AT29,30, Chang-Claude J31,32,33, Chanock SJ9, Cheng I34, Cheng YW35, Chin LS36, Church JM37, Church T38, Coetzee GA39, Cotterchio M40, Cruz Correa M41, Curtis KR4, Duggan D42, Easton DF43, English D44, Feskens EJM45, Fischer R46, FitzGerald LM44,47, Fortini BK48, Fritsche LG49,50, Fuchs CS51,52, Gago-Dominguez M53,54, Gala M29, Gallinger SJ55, Gauderman WJ2, Giles GG23,44, Giovannucci EL32,56, Gogarten SM57, Gonzalez-Villalpando C58, Gonzalez-Villalpando EM59, Grady WM60, Greenson JK61, Gsur A62, Gunter M30, Haiman CA2, Hampe J63, Harlid S64, Harju JF46, Hayes RB65, Hofer P62, Hoffmeister M14, Hopper JL66, Huang SC2, Huerta JM67, Hudson TJ68,69, Hunter DJ70, Idos GE2, Iwasaki M71, Jackson RD72, Jacobs EJ27, Jee SH73, Jenkins MA23, Jia WH74, Jiao S4, Joshi AD30,70, Kolonel LN75, Kono S22, Kooperberg C4, Krogh V76, Kuehn T77, Küry S78, LaCroix A4, Laurie CA57, Lejbkowicz F1, Lemire M69, Lenz HJ2,79, Levine D57, Li CI80, Li L81, Lieb W82, Lin Y4, Lindor NM83, Liu YR84, Loupakis F35, Lu Y85, Luh F86, Ma J87, Mancao C88, Manion FJ46, Markowitz SD89, Martin V90, Matsuda K91, Matsuo K92,93, McDonnell KJ2, McNeil CE2, Milne R23,44, Molina AJ11,94, Mukherjee B46, Murphy N95, Newcomb PA4, Offit K96, Omichessan H18,19, Palli D97, Cotoré JPP98, Pérez-Mayoral J99, Pharoah PD100, Potter JD4, Qu C2,4, Raskin L85,91, Rennert G86,101,102, Rennert HS86,101, Riggs BM1, Schafmayer C103, Schoen RE104, Sellers TA1, Seminara D105, Severi G18,106, Shi W107, Shibata D108, Shu XO85,91, Siegel EM1, Slattery ML109, Southey M24, Stadler ZK96,110, Stern MC2, Stintzing S111, Taverna D112, Thibodeau SN113, Thomas DC2, Trichopoulou A114, Tsugane S2,6,7, Ulrich CM17, van Duijnhoven FJB45, van Guelpan B, Vijai J96, Virtamo J115, Weinstein SJ9, White E4, Win AK23, Wolk A116, Woods M117, Wu AH2, Wu K118, Xiang YB119, Yen Y35,120, Zanke BW121,122, Zeng YX74, Zhang B123, Zubair N4, Kweon SS124,125, Figueiredo JC126,127, Zheng W85,91, Marchand LL5, Lindblom A128, Moreno V10,11,12, Peters U129, Casey G8, Hsu L4, Conti DV2, Gruber SB2,79.

Author information

1
Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
2
Department of Preventive Medicine, USC Norris Comprehensive Cancer Center.
3
Department of Epidemiology and Biostatistics.
4
Public Health Sciences Division.
5
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI.
6
National Cancer Center, Tokyo, Japan.
7
Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.
8
Center for Public Health Genomics, University of Virginia, Charlottesville, VA.
9
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.
10
Catalan Institute of Oncology, Bellvitge Biomedical Research Institute.
11
CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
12
University of Barcelona, Barcelona, Spain.
13
Department of Biomedical Data Science.
14
Division of Clinical Epidemiology and Aging Research.
15
Department of Epidemiology, Geisel School of Medicine, Dartmouth College, Hanover, NH.
16
Centre Hospitalier Universitaire Hotel-Dieu, Nantes, France.
17
Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, UT.
18
CESP (U1018 INSERM), Facultés de Médecine Université Paris-Sud, UVSQ, Université Paris-Saclay, Villejuif, France.
19
Gustave Roussy, Villejuif, France.
20
German Cancer Consortium.
21
National Center for Tumor Diseases (NCT), Heidelberg, Germany.
22
Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU), Nantes, France.
23
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
24
Colorectal Oncogenomics Group, Department of Pathology (DDB) and Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia.
25
Genetic Medicine and Familial Cancer Centre, The Royal Melbourne Hospital, Parkville, Victoria, Australia.
26
Division of Research, Kaiser Permanente Medical Care Program of Northern California, Oakland, CA.
27
Epidemiology Research Program, American Cancer Society, Atlanta, GA.
28
Genetic Oncology Unit, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Complejo Hospitalario Universitario de Vigo (CHUVI), SERGAS, Vigo (Pontevedra) Spain.
29
Division of Gastroenterology.
30
Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA.
31
Unit of Genetic Epidemiology, Division of Cancer Epidemiology.
32
Harvard Medical School, Boston, MA.
33
University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
34
Cancer Prevention Institute of California, Fremont, CA.
35
Ph.D. Program of Cancer Research and Drug Discovery.
36
Cancer Science Institute of Singapore, National University of Singapore, Singapore.
37
Department of Colorectal Surgery, Cleveland Clinic, Cleveland, OH.
38
Division of Environmental Health Sciences, University of Minnesota, Minneapolis, MN.
39
Van Andel Research Institute, Grand Rapids, MI.
40
Prevention and Cancer Control, Cancer Care Ontario, Toronto, ON, Canada.
41
Puerto Rico Cancer Center.
42
Genetic Basis of Human Disease Division, Translational Genomics Research Institute, Phoenix, AZ.
43
Centre for Cancer Genetic Epidemiology.
44
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia.
45
Division of Human Nutrition, Wageningen University and Research, Wageningen, the Netherlands.
46
University of Michigan Comprehensive Cancer Center, Ann Arbor, MI.
47
Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
48
W.M. Keck Science Department, Claremont Colleges, Claremont, CA.
49
Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI.
50
K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Sør-Trøndelag, Norway.
51
Department of Medical Oncology, Dana-Farber Cancer Institute, Brookline, MA.
52
Department of Medicine, Brigham and Women's Institute, Brookline, MA.
53
Genomic Medicine Group, Galician Foundation of Genomic Medicine, Complejo Hospitalario Universitario de Santiago, Servicio Galego de Saude (SERGAS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago De Compostela, Spain.
54
Moores Cancer Center, University of California San Diego, La Jolla, CA.
55
Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada.
56
Channing Division of Network Medicine, Brigham and Women's Institute, Brookline, MA.
57
Department of Biostatistics.
58
Unidad de Investigacion en Diabetes y Riesgo Cardiovascular, Centro de Investigacion en Salud Poblacional, Instituto Nacional de Salud Publica, Cuernavaca, Morelos, Mexico.
59
Centro de Estudios en Diabetes AC, Mexico City, Mexico.
60
Department of Medicine, Division of Gastroenterology, School of Medicine.
61
Department of Pathology, University of Michigan, Ann Arbor, MI.
62
Medical University of Vienna, Department of Medicine I, Institute of Cancer Research, Vienna, Austria.
63
Medical Department 1, University Hospital Dresden, TU Dresden, Dresden, Germany.
64
Department of Radiation Sciences, Oncology, Umea University, Umea, Sweden.
65
Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, NY.
66
Centre for MEGA Epidemiology, The University of Melbourne, Carlton, Victoria, Australia.
67
Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain.
68
AbbVie, Redwood City, CA.
69
Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
70
Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard School of Public Health, Boston, MA.
71
Division of Epidemiology, Center for Public Health Sciences.
72
Department of Medicine, Ohio State University, Columbus, OH.
73
Department of Epidemiology and Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, South Korea.
74
State Key Laboratory of Oncology in South China, Cancer Center, Sun Yatsen University, Guangzhou, China.
75
Office of Public Health Studies, University of Hawaii Manoa, Honolulu, HI.
76
Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
77
Division of Cancer Epidemiology.
78
Department of Preventive Medicine, Kyushu University, Fukuoka, Japan.
79
Department of Medicine, University of Southern California, Los Angeles, CA.
80
Translational Research Program, Fred Hutchinson Cancer Research Center, Seattle, WA.
81
Department of Family Medicine and Community Health, Mary Ann Swetland Center for Environmental Health, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH.
82
Institute of Epidemiology, PopGen Biobank, Christian-Albrechts-University Kiel, Kiel, Germany.
83
Department of Health Science Research, Mayo Clinic, Scottsdale, AZ.
84
Joint Biobank, Office of Human Research.
85
Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN.
86
Clalit Health Services National Israeli Cancer Control Center, Haifa, Israel.
87
Harvard School of Public Health, Boston, MA.
88
Genentech, Inc., Basel, Switzerland.
89
Departments of Medicine and Genetics, Case Comprehensive Cancer Center, Case Western Reserve University, and University Hospitals of Cleveland, Cleveland, OH.
90
Biomedicine Institute (IBIOMED), University of León, León, Spain.
91
Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN.
92
Department of Epidemiology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
93
Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Chikusa-Ku Nagoya, Japan.
94
Research Group on Gene-Environment Interactions and Health, University of León, León, Spain.
95
Nutrition and Metabolism Section, IARC, Lyon, CEDEX 08, France.
96
Clinical Genetics Service (KO), Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
97
Cancer Risk Factors and Life-Style Epidemiology Unit, Cancer Research and Prevention Institute-ISPO, Florence, Italy.
98
Department of Surgery, Complejo Hospitalario Universitario de Santiago (CHUS), Servicio Galego de Saúde (SERGAS), Santiago De Compostela, Spain.
99
Division of Cancer Biology, University of Puerto Rico, San Juan, Puerto Rico.
100
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
101
Department of Community Medicine and Epidemiology, Carmel Medical Center, Haifa, Israel.
102
Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
103
Department of Visceral and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel Campus, Kiel, Germany.
104
Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA.
105
Epidemiology and Genomics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD.
106
Human Genetics Foundation (HuGeF), Torino, Italy.
107
Department of Surgery, Children's Hospital Los Angeles, Los Angeles, CA.
108
Department of Surgery, University of Tennessee Health Science Center, Memphis, TN.
109
Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT.
110
Department of Medicine, Weill Cornell Medical Center, New York, NY.
111
Department of Hematology and Oncology University of Munich (LMU), Munich, Germany.
112
Phoenix College, Phoenix, AZ.
113
Mayo Clinic, Rochester, MN.
114
Hellenic Health Foundation, Athens, Greece.
115
Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
116
Institute of Environmental Medicine.
117
Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
118
Department of Nutrition, Harvard School of Public Health, Boston, MA.
119
State Key Laboratory of Oncogene and Related Genes and Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China.
120
Department of Medical Oncology and Therapeutic Research, City of Hope National Medical Center, Duarte, CA.
121
Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
122
The University of Ottawa, Ottawa, Ontario, Canada.
123
Division of Noncommunicable Disease Epidemiology and Southwest Hospital Clinical Research Center, Third Military Medical University, Chongqing, China.
124
Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, South Korea.
125
South Korea Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, South Korea.
126
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA.
127
Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
128
Department of Molecular Medicine and Surgery, Karolinska Institutet Solna, Stockholm, Sweden.
129
Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA.

Abstract

BACKGROUND:

Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.

METHODS:

We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.

RESULTS:

The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.

CONCLUSIONS:

This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

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